title: Adrenomedullin blockade suppresses growth of human hormone-independent prostate tumor xenograft in mice.
abstract: OBJECTIVE
  To study the role of the adrenomedullin system [adrenomedullin and its receptors (AMR), CLR, RAMP2, and RAMP3] in prostate cancer androgen-independent growth.
  
  
  METHODS
  Androgen-dependent and -independent prostate cancer models were used to investigate the role and mechanisms of adrenomedullin in prostate cancer hormone-independent growth and tumor-associated angiogenesis and lymphangiogenesis.
  
  
  RESULTS
  Adrenomedullin and AMR were immunohistochemically localized in the carcinomatous epithelial compartment of prostate cancer specimens of high grade (Gleason score >7), suggesting a role of the adrenomedullin system in prostate cancer growth. We used the androgen-independent Du145 cells, for which we demonstrate that adrenomedullin stimulated cell proliferation in vitro through the cAMP/CRAF/MEK/ERK pathway. The proliferation of Du145 and PC3 cells is decreased by anti-adrenomedullin antibody (αAM), supporting the fact that adrenomedullin may function as a potent autocrine/paracrine growth factor for prostate cancer androgen-independent cells. In vivo, αAM therapy inhibits the growth of Du145 androgen-independent xenografts and interestingly of LNCaP androgen-dependent xenografts only in castrated animals, suggesting strongly that adrenomedullin might play an important role in tumor regrowth following androgen ablation. Histologic examination of αAM-treated tumors showed evidence of disruption of tumor vascularity, with depletion of vascular as well as lymphatic endothelial cells and pericytes, and increased lymphatic endothelial cell apoptosis. Importantly, αAM potently blocks tumor-associated lymphangiogenesis, but does not affect established vasculature and lymphatic vessels in normal adult mice.
  
  
  CONCLUSIONS
  We conclude that expression of adrenomedullin upon androgen ablation in prostate cancer plays an important role in hormone-independent tumor growth and in neovascularization by supplying/amplifying signals essential for pathologic neoangiogenesis and lymphangiogenesis. Clin Cancer Res; 19(22); 6138-50. ©2013 AACR.
authors.affiliation: Authors' Affiliations: Aix-Marseille Université and Insitut national de la santé et de la recherche medicale (INSERM), CRO2 UMR 911, 13005; AP-HM, CHU Nord, Service Urologie, 13015; Aix-Marseille Université, LCP UMR 6264, CROPS, 13397; and AP-HM, CHU Nord, Service de Transfert d'Oncologie Biologique, 13015, Marseille, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Berenguer-Daizé
authors.forename: Françoise
authors.initials: F
authors.lastname: Boudouresque
authors.forename: Cyrille
authors.initials: C
authors.lastname: Bastide
authors.forename: Asma
authors.initials: A
authors.lastname: Tounsi
authors.forename: Zohra
authors.initials: Z
authors.lastname: Benyahia
authors.forename: Julie
authors.initials: J
authors.lastname: Acunzo
authors.forename: Nadège
authors.initials: N
authors.lastname: Dussault
authors.forename: Christine
authors.initials: C
authors.lastname: Delfino
authors.forename: Nathalie
authors.initials: N
authors.lastname: Baeza
authors.forename: Laurent
authors.initials: L
authors.lastname: Daniel
authors.forename: Mylène
authors.initials: M
authors.lastname: Cayol
authors.forename: Dominique
authors.initials: D
authors.lastname: Rossi
authors.forename: Assou
authors.initials: A
authors.lastname: El Battari
authors.forename: Denis
authors.initials: D
authors.lastname: Bertin
authors.forename: Kamel
authors.initials: K
authors.lastname: Mabrouk
authors.forename: Pierre-Marie
authors.initials: PM
authors.lastname: Martin
authors.forename: L'houcine
authors.initials: L
authors.lastname: Ouafik
mesh_terms: D053607:Adrenomedullin / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D000728:Androgens; D000818:Animals; D000906:Antibodies / Q000276:immunology; D017209:Apoptosis / Q000276:immunology; D058286:Calcitonin Receptor-Like Protein; D002352:Carrier Proteins / Q000378:metabolism; D002369:Castration; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology; D049109:Cell Proliferation; D000242:Cyclic AMP / Q000378:metabolism; D042783:Endothelial Cells / Q000276:immunology; D006801:Humans; D042583:Lymphangiogenesis; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D020286:Pericytes / Q000276:immunology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000378:metabolism*; D058263:Receptor Activity-Modifying Protein 2 / Q000378:metabolism; D058264:Receptor Activity-Modifying Protein 3 / Q000378:metabolism; D058265:Receptors, Adrenomedullin / Q000276:immunology; D018003:Receptors, Calcitonin / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D014183:Transplantation, Heterologous
chemical_list: D000728:Androgens; D000906:Antibodies; C545578:CALCRL protein, human; D058286:Calcitonin Receptor-Like Protein; D002352:Carrier Proteins; C533270:NSMCE1 protein, human; C545503:RAMP2 protein, human; C545504:RAMP3 protein, human; D058263:Receptor Activity-Modifying Protein 2; D058264:Receptor Activity-Modifying Protein 3; D058265:Receptors, Adrenomedullin; D018003:Receptors, Calcitonin; D053607:Adrenomedullin; D000242:Cyclic AMP